Various disorders of warm-blooded animals are linked with an excess of metals, in particular trivalent metals, in the body tissues. For example, aluminum in dialysis encephalopathy and osteomalacia, as well as in Alzheimer""s disease is representative. In other illnesses, in particular of man, an excess of iron occurs in the various tissues. This is designated as iron overload (formerly haemosiderosis). It occurs, e.g., after parenteral administration of iron (especially repeated blood transfusions) or after increased uptake of iron from the gastrointestinal tract. Repeated transfusions are necessary in serious anemias, especially in thalassaemia major, the severe form of xcex2-thalassaemia, but also in other anemias. Increased iron absorption from the gastrointestinal tract either takes place primarily, e.g. on account of a genetic defect (so-called haemochromatosis), or secondarily, such as after anemias in which blood transfusions are not necessary, e.g. thalassaemia intermedia, a milder form of xcex2-thalassaemia.
Untreated iron overload can cause severe organ damage, in particular of the liver, the heart and the endocrine organs, and can lead to death. Iron chelators are able to mobilize and excrete the iron deposited in the organs and thus lower the iron-related morbidity and mortality.
A reduction in the iron(III) concentration is also of interest for the treatment of disorders due to iron(III)-dependent microorganisms and parasites, which is of key importance not only in human medicine, such as in particular in malaria, but also in veterinary medicine. Complexing of other metals, in particular trivalent metals, can also be used for excretion thereof from the organism. A number of further applications are also described in the literature, e.g. by Kontoghiorghes, Toxicology Lett. 80:1-18 (1995).
Desferrioxamine B has already been known for a long time and used therapeutically for these purposes [Bickel et al., Helv. Chim. Acta 46:1385-1389 (1963)]. A disadvantage of this preparation, however, turns out to be the fact that desferrioxamine and its salts only have a low, inadequate activity on oral administration and require a parenteral administration form in all of the abovementioned application possibilities. It is thus recommended, e.g., as a particularly effective method to administer the active substance by means of a slow (8 to 12 hour) subcutaneous infusion, which, however, demands the use of a portable mechanical device, such as an infusion syringe actuated by an electrical drive. Apart from their awkwardness, such solutions are affected by a high treatment cost, which severely restricts their use; in particular a comprehensive treatment of the thalassaemias in the countries of the Mediterranean region, of the Middle East, India and South-East Asia, of malaria worldwide and of sickle-cell anemia in African countries is made impossible. These widespread diseases are furthermore a serious problem for the health service in these countries and make the search for a simpler and more inexpensive therapy, preferably by means of an orally active preparation, the urgent object in this area.
Various 3,5-diphenyl-1,2,4-triazoles have been known for a long time and their use is described for herbicides, e.g. in EP 185,401, as angiotensin II receptor antagonists in EP 480,659, or very generally as intermediates and starting compounds for fine chemicals, e.g. in JP 06345728.
It has now been found that certain substituted 3,5-diphenyl-1,2,4-triazoles have valuable pharmacological properties when used in the treatment of disorders which cause an excess of metal in the human or animal body or are caused by it, primarily a marked binding of trivalent metal ions, in particular those of iron [Martell and Motekaitis, Determination and Use of Stability Constants, VCH Publishers, New York (1992)]. They are able, e.g. in an animal model using the non-iron overloaded cholodocostomized rat [Bergeron et al., J. Med. Chem. 34:2072-2078 (1991)] or the iron-overloaded monkey [Bergeron et al., Blood 81:2166-2173 (1993)] in doses from approximately 5 xcexcmol/kg, inter alia, to prevent the deposition of iron-containing pigments and in the case of existing iron deposits in the body cause excretion of the iron.
The present invention relates to the use of compounds of the formula I 
in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile; R2 and R4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g. a protective group; R3 is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R6R7Nxe2x80x94C(O)-lower alkyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted heteroaryl or heteroaralkyl; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and salts thereof; in the treatment of diseases which cause an excess of metal in the human or animal body or are caused by it; preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to a treatment method of this type.
Halogen is, e.g., chlorine, bromine or fluorine, but can also be iodine.
The prefix xe2x80x9clowerxe2x80x9d designates a radical having not more than 7 and in particular not more than 4 carbon atoms.
Alkyl is straight-chain or branched. Per se, e.g. lower alkyl, or as a constituent of other groups, e.g. lower alkoxy, lower alkylamine, lower alkanoyl, lower alkylaminocarbonyl, it can be unsubstituted or substituted, e.g. by halogen, hydroxyl, lower alkoxy, trifluoromethyl, cyclo-lower alkyl, azaalicyclyl or phenyl, it is preferably unsubstituted or substituted by hydroxyl.
Lower alkyl is, e.g., n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl and n-propyl. Halo-lower alkyl is lower alkyl substituted by halogen, preferably chlorine or fluorine, in particular by up to three chlorine or fluorine atoms.
Lower alkoxy is, e.g., n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-amyloxy, isoamyloxy, preferably methoxy and ethoxy. Halo-lower alkoxy is lower alkoxy substituted by halogen, preferably chlorine or fluorine, in particular by up to three chlorine or fluorine atoms.
Carbamoyl is the radical H2Nxe2x80x94C(O)xe2x80x94, N-lower alkylcarbamoyl is lower alkyl-HNxe2x80x94C(O)xe2x80x94and N,N-di-lower alkylcarbamoyl is di-lower alkyl-Nxe2x80x94C(O)xe2x80x94.
Lower alkanoyl is HC(O)xe2x80x94 and lower alkyl-C(O)xe2x80x94 and is, e.g., acetyl, propanoyl, butanoyl or pivaloyl.
Lower alkoxycarbonyl designates the radical lower alkyl-Oxe2x80x94C(O)xe2x80x94 and is, e.g., n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-amyloxycarbonyl, isoamyloxycarbonyl, preferably methoxycarbonyl and ethoxycarbonyl.
Aryl, per se, e.g. aryl, or as a constituent of other groups, e.g. aryl-lower alkyl or aroyl, is, e.g., phenyl or naphthyl, which is substituted or unsubstituted. Aryl is preferably phenyl which is unsubstituted or substituted by one or more, in particular one or two, substituents, e.g. lower alkyl, lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, heterocycloalkyl, heteroaryl or cyano. Primarily, aryl is unsubstituted phenyl or naphthyl, or phenyl which is substituted by lower alkyl, lower alkoxy, hydroxyl, halogen, carboxyl, lower alkoxycarbonyl, N, N-di-lower alkylamino or heterocycloalkylcarbonyl.
Aroyl is the radical aryl-C(O)xe2x80x94 and is, e.g., benzoyl, toluoyl, naphthoyl or p-methoxybenzoyl. Aryl-lower alkyl is, e.g., benzyl, p-chlorobenzyl, o-fluorobenzyl, phenylethyl, p-tolylmethyl, p-dimethylaminobenzyl, p-diethylaminobenzyl, p-cyanobenzyl, p-pyrrolidinobenzyl. Heterocycloalkyl designates a cycloalkyl radical having 3 to 8, in particular having from 5 to not more than 7, ring atoms, of which at least one is a heteroatom; oxygen, nitrogen and sulfur are preferred. Azaalicyclyl is a saturated cycloalkyl radical having 3-8 in particular 5-7, ring atoms, in which at least one of the ring atoms is a nitrogen atom. Azaalicyclyl can also contain further ring heteroatoms, e.g. oxygen, nitrogen or sulfur; it is, e.g., piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl. Azaalicyclyl radicals can be unsubstituted or substituted by halogen or lower alkyl. The azaalicyclyl radicals bonded via a ring nitrogen atom, which are preferred, are, as is known, designated as piperidino, piperazino, morpholino, pyrrolidino etc.
Heteroaryl per se, e.g. heteroaryl, or as a constituent of other substituents, e.g. heteroaryl-lower alkyl, is an aromatic radical having from 3 to not more than 7, in particular from 5 to not more than 7, ring atoms, in which at least one of the ring atoms is a heteroatom, e.g. pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, oxazinyl, thiazinyl, pyranyl or pyrimidinyl. Heteroaryl can be substituted or unsubstituted. Heteroaryl which is unsubstituted or substituted by one or more, in particular one or two, substituents, e.g. lower alkyl, halogen, trifluoromethyl, carboxyl or lower alkoxycarbonyl, is preferred.
Heteroaryl-lower alkyl designates a lower alkyl radical in which at least one of the hydrogen atoms, preferably on the terminal C atom, is replaced by a heteroaryl group if the alkyl chain contains two or more carbon atoms. N-lower alkylamino is, e.g., n-propylamino, n-butylamino, i-propylamino, i-butylamino, hydroxyethylamino, preferably methylamino and ethylamino. In N,N-di-lower alkylamino, the alkyl substituents can be identical or different. Thus N,N-di-lower alkylamino is, e.g., N,N-dimethylamino, N,N-diethylamino, N,N-methylethylamino, N-methyl-N-morpholinoethylamino, N-methyl-N-hydroxyethylamino or N-methyl-N-benzylamino.
Salts of compounds of the formula I are, in particular, pharmaceutically acceptable salts, especially salts with bases, such as appropriate alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts such as zinc salts, or salts with organic amines, such as cyclic amines, such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkylamines, e.g. mono-, di- or trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-lower alkylamines. Cyclic amines are, e.g., morpholine, thiomorpholine, piperidine or pyrrolidine. Suitable mono-lower alkylamines are, e.g., ethyl- and tert-butylamine; di-lower alkylamines are, e.g., diethyl- and diisopropylamine; and tri-lower alkylamines are, e.g., trimethyl- and triethylamine. Appropriate hydroxy-lower alkylamines are, e.g., mono-, di- and triethanolamine; hydroxy-lower alkyl-lower alkylamines are, e.g., N,N-dimethylamino- and N,N-diethylaminoethanol; a suitable polyhydroxy-lower alkylamine is, e.g., glucosamine. In other cases it is also possible to form acid addition salts, e.g. with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g. acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or such as hydroxycarboxylic acids, e.g. tartaric or citric acid, or with sulfonic acids, such as lower alkane- or substituted or unsubstituted benzenesulfonic acids, e.g. methane- or p-toluenesulfonic acid. Compounds of the formula I having an acidic group, e.g. carboxyl, and a basic group, e.g. amino, can also be present in the form of internal salts, i.e. in zwitterionic form, or a part of the molecule can be present as an internal salt, and another part as a normal salt.
In particular, the invention relates to the use of a compound of formula I for the treatment of diseases which cause an excess of iron in the human or animal body or are caused by it, preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to a treatment method of this type.
In addition, the invention relates to novel preparations, comprising at least one compound of the formula I, in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile; R2 and R4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g. a protective group; R3 is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R6R7Nxe2x80x94C(O)-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and salts thereof; and at least one pharmaceutically acceptable carrier; and to methods for their preparation. These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being contained on its own or together with customary pharmaceutical adjuncts. The pharmaceutical preparations contain (in percentages by weight), e.g., from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 100%, of the active ingredient.
Pharmaceutical preparations for enteral or parenteral administration are, e.g., those in unit dose forms, such as sugar-coated tablets, tablets, dispersible tablets, effervescent tablets, capsules, suspendable powders, suspensions or suppositories, or ampoules. These are prepared in a manner known per se, e.g. by means of conventional pan-coating, mixing, granulation or lyophilization processes. Pharmaceutical preparations for oral administration can thus be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained and processing the mixture or granules, if desired or necessary, after addition of suitable adjuncts to give tablets or sugar-coated tablet cores.
Suitable carriers are, in particular, fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch pastes, using, e.g., maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are primarily flow-regulating and lubricating agents, e.g. salicylic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable, if desired enteric, coatings, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enterc coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, e.g. for the identification or the marking of various doses of active ingredient, can be added to the tablets or sugar-coated tablet coatings.
Dispersible tablets are tablets which rapidly disintegrate in a comparatively small amount of liquid, e.g. water, and which, if desired, contain flavorings or substances for masking the taste of the active ingredient. They can advantageously be employed for the oral administration of large individual doses, in which the amount of active ingredient to be administered is so large that on administration as a tablet which is to be swallowed in undivided form or without chewing that it can no longer be conveniently ingested, in particular by children. Further orally administrable pharmaceutical preparations are hard gelatin capsules and also soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules can contain the active ingredient in the form of granules, e.g. as a mixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilizers. Moreover, suspendable powders, e.g. those which are described as xe2x80x9cpowder in bottlexe2x80x9d, abbreviated xe2x80x9cPIBxe2x80x9d, or ready-to-drink suspensions, are suitable for an oral administration form. For this form, the active ingredient is mixed, e.g., with pharmaceutically acceptable surface-active substances, e.g., sodium lauryl sulfate or polysorbate, suspending auxiliaries, e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and previously described, e.g., in xe2x80x9cHandbook of Pharmaceutical Ecipientsxe2x80x9d, pH regulators, such as citric or tartaric acid and their salts or a USP buffer and, if desired, fillers, e.g. lactose, and further auxiliaries, and dispensed into suitable vessels, advantageously single-dose bottles or ampoules. Immediately before use, a specific amount of water is added and the suspension is prepared by shaking. Alternatively, the water can also be added even before dispensing.
Rectally administrable pharmaceutical preparations are, e.g., suppositories which consist of a combination of the active ingredient with a suppository base. A suitable suppository base is, e.g., natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules can also be used which contain a combination of the active ingredient with a base substance. Possible base substances are, e.g., liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. of a water-soluble salt, are primarily suitable; furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, being used, or aqueous injection suspensions which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, also stabilizers.
The dosage of the active ingredient can depend on various factors, such as activity and duration of action of the active ingredient, severity of the illness to be treated or its symptoms, manner of administration, warm-blooded animal species, sex, age, weight and/or individual condition of the warm-blooded animal. The doses to be administered daily in the case of oral administration are between 10 and approximately 120 mg/kg, in particular 20 and approximately 80 mg/kg, and for a warm-blooded animal having a body weight of approximately 40 kg, preferably between approximately 400 mg and approximately 4,800 mg, in particular approximately 800 mg to 3,200 mg, which is expediently divided into 2 to 12 individual doses.
Preferably, the invention relates to novel preparations comprising at least one compound of the formula I in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy; R2 and R4 simultaneously or independently of one another are hydrogen or a radical which can be removed under physiological conditions, e.g. a protective group; R3 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R6R7Nxe2x80x94C(O)-lower alkyl, substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and salts thereof; and at least one pharmaceutically acceptable carrier, and to methods for their preparation. These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration, and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being present on its own or together with customary pharmaceutical adjuncts. The pharmaceutical preparations contain (in percentages by weight), e.g., from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 50%, of the active ingredient.
The present invention also makes available novel compounds of the general formula I 
in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen, lower-alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile; R2 and R4 simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g. a protective group; R3 is R6R7Nxe2x80x94C(O)-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroaralkyl, with the proviso that R3 is not phenyl or phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or lower alkoxycarbonyl if R2 and R4 are hydrogen, and R1 and R5 are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoXY or nitrile; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring;
and salts thereof.
Primarily, the invention relates to compounds of the formula I in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy; R2 and R4 simultaneously or independently of one another are hydrogen or a radical which can be removed under physiological conditions, e.g. a protective group; R3 is R6R7Nxe2x80x94C(O)-lower alkyl, substituted aryl, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkyl amino or pyrrolidino, or unsubstituted or substituted heteroaralkyl with the proviso that R3 is not phenyl, substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy or lower alkoxycarbonyl, if R2 and R4 are hydrogen and R1 and R5 are hydrogen, halogen, lower alkyl, halo-lower alkyl or lower alkoxy; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and salts thereof.
In particular, the invention relates to compounds of the formula II in which
R1 and R5 simultaneously or independently of one another are hydrogen, halogen or lower alkyl; R2 and R4 are hydrogen; R3 is R6R7Nxe2x80x94C(O)-lower alkyl, substituted aryl, substituted by carboxyl or R8R9Nxe2x80x94C(O)-, aryl-lower alkyl, substituted by N-lower alkylamino, N,N-di-lower alkylamino or pyrrolidino, or unsubstituted or substituted heteroaralkyl; R6 and R7 simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl or N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; R8 and R9 simultaneously or independently of one another are hydrogen or lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and pharmaceutically acceptable salts thereof.
The invention relates especially to the specific compounds of the formula II and their salts, in particular their pharmaceutically acceptable salts, described in the examples.
The compounds can be prepared in a manner known per se by, e.g.,
a) reacting a compound of the formula III 
in which R1, R2, R4 and R5 are as defined above and Xxe2x88x92 is an anion, with a compound of the formula IV
R3xe2x80x94NHxe2x80x94NH2xe2x80x83xe2x80x83(IV)
in which R3 is as defined above, or a salt thereof; or
b) reacting a compound of the formula V 
in which R1, R4 and R5 are as defined above, or a salt thereof, with a compound of the formula IV
in which R3 is as defined above, or a salt thereof; or
c) reacting a compound of the formula VI 
in which R1, R2, R4 and R5 are as defined above, with a compound of the formula IV in which R3 is as defined above, or a salt thereof;
and then converting this compound, if necessary, into a compound of the formula II by removal of protective groups, and, if desired, converting it into another compound of the formula II and/or, if desired, converting a salt obtained into the free compound or into another salt, and/or, if desired, converting a free compound of the formula II obtained and having salt-forming properties into a salt.
In the following more detailed description of the process, the symbols R1-R5 are as defined under the formulae II, III, IV, V and VI, if not stated otherwise.
Process (a)
The reaction according to process (a) corresponds to the ring rearrangement reaction of 1,2,4-dithiazolidines to 1,2,4-triazoles, with hydrazines, which is known per se [Wagner et al., Pharmazie 35:48-49 (1980)]. Xxe2x88x92 can be any desired anion, preferably a halogen anion, in particular a bromine anion. The reaction can take place with or without solvents, advantageously it is carried out in a polar solvent or solvent mixture, in this case the compound IV can be present as such or alternatively as a solvate, in particular as a hydrate. The reaction proceeds with cooling, at ambient temperature or elevated temperature up to the reflux temperature of the reaction mixture. It is preferably carried out at ambient temperature or elevated temperature.
Process (b)
The reaction according to process (b) corresponds to the reaction of benzoxazinones with hydrazines, which is known per se [Wagner et al., Z. Chem. 21:261 (1981) and Ryabukhin et al, Khim. Geterotsiklicheskikh Soed. (3), 406-410 (1983)]. The reaction is carried out in a polar solvent or solvent mixture, preferably in a lower alkanol, in particular methanol or ethanol, if desired with addition of a base, such as a tertiary amine, in particular tri-lower alkylamine, if the compound III and/or IV is present as a salt, e.g. as a hydrohalide. The reaction proceeds with cooling, at ambient temperature or at elevated temperature up to the reflux temperature of the reaction mixture. In a particularly preferred embodiment, the reaction is carried out under reflux in ethanol.
The starting compounds V are accessible, e.g., by the reaction of appropriately substituted salicylic acid with appropriately substituted salicylamide in the presence of thionyl chloride (CH 388252 and Brunetti and Lxc3xcthi, Helv. Chim. Acta 55:1566 (1972)]. In addition, the starting compounds V can be prepared by heating a mixture of appropriately substituted salicyloyl chloride with suitably substituted salicylamide.
Process (c)
Process (c) corresponds to the reaction of diacylamines with hydrazines, which is known per se [Einhorn et al., Liebigs Ann. Chem. 343:229 (1905), Brunner, Ber. dtsch. chem. Ges. 47:2671 (1914) and Brunner, Mh. Chem. 36:509 (1915)]. The reaction takes place in polar, protic solvents under weak acid catalysis, preferably in aqueous acetic acid at elevated temperature.
The compounds of the formula II can also be prepared according to further processes which are known per se, e.g. according to the processes which are described by Temple, in: The Chemistry of Heterocyclic Compounds, Vol. 37, John Wiley and Sons, New York (1981).
Protective groups, their introduction and removal are described, e.g., in McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York (1973), and in Methoden der organischen Chemie [Methods of organic chemistry], Houben-Weyl, 4th Edition, Vol. 1571, Georg Thieme, Stuttgart (1974), and also in Greene, Protective Groups in Organic Synthesis, John Wiley, New York (1981). It is characteristic of protective groups that they can be removed easily, i.e. without undesired side reactions taking place, e.g. solvolytically, reductively, photolytically or alternatively under physiological conditions.
Hydroxyl groups can be present, e.g., in the form of an easily cleavable ester or ether group, preferably of an alkanoyl or aralkanoyl ester group or of a cycloheteroalkyl, aralkyl or alkoxyalkyl ether group, but also of a silyl ester or silyl ether group, in particular as an acetyl or benzoyl ester or as a tetrahydropyranyl, benzyl or methoxymethyl ether.
The starting materials of the formulae III, IV, V and VI are novel in some cases and likewise a subject of the present invention. If necessary, suitable protective groups can be introduced or further derivatization can be carried out according to known methods.
The protective groups which are not a constituent of the desired final product of the formula II are removed in a manner known per se, e.g. by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, optionally stepwise or simultaneously.
Compounds of the formula II can also be converted into other compounds of the formula II or the formula I.
Thus it is possible to hydrolyze, e.g., a compound of the formula II in which R3 is an aryl-carboxylic acid ester radical, to the corresponding arylcarboxylic acid, a compound of the formula II being obtained in which R3 is a carboxylic acid radical. The reaction is carried out, e.g., in a polar solvent mixture of a cyclic ether and an alkanol with addition of an alkali metal hydroxide.
When starting compounds of the formula I or any intermediates contain interfering reactive groups, e.g. carboxyl, hydroxyl or amino groups, these can be temporarily protected by easily removable protective groups.
To work up the compounds of the formula II obtainable or their salts and, if necessary, the intermediates, customary processes are used, e.g. solvolysis of excess reagents; recrystal-lization, chromatography, e.g. partition, ion or gel chromatography, partition between an in-organic and organic solvent phase; single or multiple extraction, in particular after acidification or increasing the basicity or the salt content, drying over hygroscopic salts or at elevated temperature, if desired with passing through or passing by of a gas stream; digestion; filtration; washing; dissolution; evaporation (if necessary in a vacuum or high vacuum); distillation; precipitation; centrifugation; crystallization, e.g. of compounds obtained in oil form or from the mother liquor, it also being possible to seed the final product with a crystal; lyophilization; or a combination of two or more of the working-up steps mentioned, which can also be employed repeatedly; etc.
Starting materials and intermediates can be used in pure form, e.g. after working up, as last-mentioned, in partially purified form or alternatively, e.g., directly as crude products.
The compounds, including their salts, can also be obtained in the form of hydrates or solvates, or their crystals can include, e.g., the solvent used for crystallization.
Solvents and diluents are, e.g., water, alcohols, e.g. lower alkanols, such as methanol, ethanol, propanol, butanol or ethylene glycol monomethyl ether (methylcellosolve), diols, such as ethylene glycol, tri- or polyols, such as glycerol or diethylene glycol, or aryl alcohols, such as phenol or benzyl alcohol, acid amides, e.g. carboxamides, such as N,N-dimethylformamide, or N,N-dimethylacetamide, amides of inorganic acids, such as hexamethylphosphoramide, ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower alkanes, e.g. methylene chloride or chloroform, ketones, such as acetone, nitrites, such as acetonitrile, esters, such as ethyl acetate, bisalkane sulfoxides, such as dimethyl sulfoxide, nitrogen heterocycles, such as N-methylpyrrolidone or pyridine, hydrocarbons, e.g. lower alkanes, such as hexane or heptane, or aromatics, such as benzene, toluene or xylene(s), or mixtures of these solvents, it being possible for the suitable solvents in each case for the abovementioned reactions and working-up steps to be selected.
In the process of the present invention, those starting substances and intermediates, in each case in free form or in salt form, are preferably used which lead to the compounds II or their salts described as particularly valuable at the outset. Novel starting substances and intermediates, in each case in free form or in salt form, for the preparation of the compounds II or their salts, their use and processes for their preparation also form a subject of the invention.
The invention also relates to those embodiments of the process in which a compound obtainable in any desired process stage as an intermediate is used as a starting material and the missing process steps are carried out, or in which a starting substance is formed under the reaction conditions or is used in the form of a derivative, e.g. of a salt thereof.
Salts of compounds II can be prepared in a manner known per se. Thus acid addition salts, e.g., of compounds II are obtained by treatment with a suitable acid or a suitable ion-exchange reagent and salts with bases are obtained by treatment with a suitable base or a suitable ion-exchange reagent. Salts of compounds of the formula II can be converted in a customary manner into the free compounds II; acid addition salts can be converted, e.g., by treatment with a suitable basic agent or a suitable ion-exchange reagent; and salts with bases can be converted, e.g., by treatment with a suitable acid or a suitable ion-exchange reagent.
Salts of compounds II can be converted into other salts of compounds II in a manner known per se; acid addition salts can be converted, e.g., into other acid addition salts, e.g. by treatment of a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as a sodium, barium or silver salt, of another acid, e.g. silver acetate, in a suitable solvent, in which an inorganic salt formed, e.g. silver chloride, is insoluble and thus precipitates from the reaction mixture.
Depending on the procedure or reaction conditions, the compounds II with salt-forming properties can be obtained in free form or in the form of salts.
As a result of the close relationship between the compound II in free form and in the form of its salts, in what has been said above and what follows, the free compound II or its salts are, if appropriate, to be understood analogously and expediently as also meaning the corresponding salts or the free compound II.
The compounds II including their salts of salt-forming compounds can also be obtained in the form of their hydrates and/or include other solvents, e.g., if appropriate, solvents used for the crystallization of compounds present in solid form.
The compounds II and their salts, depending on the choice of the starting substances and working procedures, can be present in the form of one of the possible isomers, e.g. stereoisomers or tautomers, or as a mixture thereof. In this context, pure isomers obtainable are, e.g., pure enantiomers, pure diastereoisomers or pure tautomers. Correspondingly, isomer mixtures which can be present are, e.g., racemates or diastereoisomer mixtures. Isomer mixtures of compounds II in free form or in salt form obtainable according to the process or in other ways can be separated into the components in a customary manner, e.g. on the basis of the physicochemical differences of the constituents, in a known manner by fractional crystallization, distillation and/or chromatography. Advantageously, the more active isomer is isolated.
The following examples are intended to illustrate the invention described above, but without restricting it to them. (Above and below, the following abbreviationsxe2x80x94if not stated otherwisexe2x80x94are used: h, hour(s); m.p., melting point; DMSO- d6, hexadeuterodimethyl sulfoxide)